The present invention relates to the field of atherosclerosis intervention. More specifically, the invention relates to near-infrared imaging for in vivo identification and characterization of tissue including vulnerable atherosclerotic plaques.
Over the past two decades, valuable studies have been conducted using new intracoronary technologies to characterize coronary lesions in living patients. These new technologies include angioscopy, ultrasound, and atherectomy. Studies based upon these approaches have further added to the knowledge gained from post-mortem studies. While much has been learned during post-mortem studies, by definition, these investigations cannot provide prospective data. Furthermore, the procedures used in living patients, cannot usually provide detailed information on the chemical composition of the diseased tissue. A significant amount of relevant information, however, has been derived over the years through various studies on coronary lesions.
The characterization of lesions causing acute coronary syndromes has been advanced significantly by post-mortem observations. It was earlier observed that in human autopsy specimens of thrombosed coronary arterial segments, the thrombus was situated at the site of a plaque where an intimal fracture allowed the exposure of soft, abscess-like lipoid material into the lumen of the blood vessel (Constantinides P, Plaque fissures in human coronary thrombosis, J Atheroscler Res 1966; 6:1-17 (cited references are incorporated herein by reference)). Subsequently, it was shown that coronary thrombi responsible for fatal myocardial infarction were almost exclusively found at the site of disrupted plaques (Davies M J, Thomas A C, Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death, N Engl J Med 1984; 310:1137-40; Davies M J, A macro and micro view of coronary vascular insult in ischemic heart disease, Cir 1990; 82(3):38-46; Falk E, Plaque rupture with severe pre existing stenosis precipitating coronary thrombosis: Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi, Br Heart 1983; 50:127-34). The lipid content of human aortic plaques displaying ulceration and thrombosis was observed to be greater than that of non-disrupted plaques. Similarly, in patients dying of acute myocardial infarction, previous research revealed that while culprit lesion morphology in myocardial infarction is heterogeneous with respect to plaque architecture and cellular composition (van der Wal A C, Becker A E, van der Loos C M, Das P K, Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology, Circulation 1994; 89:36-44), the immediate site of plaque rupture is marked by an inflammatory process. An incidence of plaque disruption of about 83% has been also reported, similar to that of infarction, in patients with unstable angina. Additional reports noted the occurrence of coronary thrombosis at sites that do not show typical signs of plaque rupture (Burke A P, Farb A, Malcom G T, Liang Y-H, Smialek J, Virmani R, Coronary risk factors and plaque morphology in men with coronary disease who died suddenly, N Engl J Med 1997; 336:1276-82). These have been termed sites of erosion, and it is estimated that they are responsible for approximately 30% of coronary thrombi, with plaque rupture accounting for the remainder. There is a frequent occurrence in these studies of lipid-rich plaques with thin caps, both ruptured and non-ruptured, as incidental findings in patients dying of other coronary lesions, or non-cardiac causes (Falk E, Shah P K, Fuster V, Coronary plaque disruption, Circ. 1995; 92:657-71). It has also been observed that approximately 80% of patients dying suddenly had such lesions in addition to their culprit lesions (Farb A, Burke A P, Tang A L et al, Coronary plaque erosion without rupture into a lipid core: A frequent cause of coronary thrombosis in sudden coronary death, Circulation 1996; 93:1354-63). Although many post-mortem studies have yielded valuable information, there are several important limitations to their use. Because of possible selection bias, the findings derived from autopsy studies can be generalized with certainty only to those who die of acute coronary syndromes. It is quite possible that the prevalence, nature, and degree of plaque disruption and/or associated thrombosis of culprit lesions, is different in those surviving the disease. Results from autopsy studies suggest nonetheless that most acute lesions arise from a plaque that includes a lipid pool, a thin cap, and macrophage infiltration. While prospective studies have been limited, these histologic features may be considered to represent a xe2x80x9cvulnerable plaquexe2x80x9d, a term first defined by Muller et al (Muller J E et al, Triggers, Acute Risk Factors and Vulnerable Plaques: The Lexicon of a New Frontier, JACC 1994; 23(3) 809-13). This type of plaque refers to its functional property of having an increased likelihood of rupture, and may include more than one histologic type.
The coronary angiogram is considered a primary source of information for living patients with lesions that cause acute coronary syndromes. Recently, retrospective analysis of coronary angiograms in patients who subsequently developed unstable angina and myocardial infarction demonstrated that many culprit lesions originate from plaques previously causing less than 50% stenosis (Ambrose J A, Tannenbaum M A, Alexopoulos D et al, Angiographic progression of coronary artery disease and the development of myocardial infarction, J Am Coll Cardiol 1988; 12, 56-62; Ambrose J A, Winters S L, Arora R R et al, Angiographic evolution of coronary artery morphology in unstable angina, J Am Coll Cardiol 1986; 5,472-8; Nobuyoshi M, Tanaka M, Nosaka H et al, Progression of coronary atherosclerosis: is coronary spasm related to progression? J Am Coll Cardiol 1991; 18, 904-10; Little W C, Downes T R, Applegate R J, The underlying coronary lesion in myocardial infarction: implications for coronary angiography, Clin Cardiol 1991; 14, 868-74). The residual stenosis, after successful thrombolytic therapy, was found to be of only moderate severity in many cases, supporting the concept that occlusive thrombus frequently develops at coronary sites without prior severe stenosis (Kereiakes D J, Topol E J, Sea G, Myocardial infarction with minimal coronary atherosclerosis in the era of thrombolytic reperfusion, J Am Coll Cardiol 1991; 17, 304-12; Brown G G, Gallary C A, Badger R S et al, Incomplete lysis of thrombus in the moderate underlying atherosclerotic lesion during intracoronary infusion of streptokinase for acute myocardial infarction, Circulation 1986; 73, 653-61). Despite these advances, the use of coronary angiography to study coronary atherosclerotic lesions in living patients has severe limitations including its inability to provide information about the sub-surface features of the plaque. The relatively low sensitivity and specificity of a plaque""s geometric surface features to predict subsequent occlusion indicate that other plaque-related characteristics (i.e., plaque composition), not detectable by angiography, may be more important in the determination of plaque vulnerability (Taeymans Y, Theroux P, Lesperance J, Waters D, Quantitative angiographic morphology of the coronary artery lesions at risk of thrombotic occlusion, Circulation 1992; 85, 78-85).
The development of angioscopic imaging devices for the coronary arteries also provided a valuable opportunity to define the surface features of lesions which cause unstable angina and acute coronary syndromes. Angioscopic imaging devices were used percutaneously to obtain a clear view, with magnification, of the inner surface of the coronary lumen in patients undergoing catheterization. Normal segments of coronary arteries in living patients were observed to be white and smooth, while disrupted atherosclerotic plaques causing disease were elevated and, in many cases, yellow and/or red in color (Mizuno K, Miyamoto A, Satomura K et al, Angioscopic coronary macromorphology in patients with acute coronary disorders, Lancet 1991; 337, 809-12). Imaging of the site of percutaneous transluminal coronary angioplasty (PTCA) also permitted identification of the mechanism of abrupt closure (Sassower M A, Abela G S, Koch J M et al, Angioscopic evaluation of peri-procedural and post-procedural abrupt closure following percutaneous coronary angioplasty, Am Heart J 1993). A study using angioscopy demonstrated that patients with xe2x80x9cglistening yellowxe2x80x9d plaques had a 68% incident rate within the subsequent year of unstable angina or myocardial infarction, as opposed to a 4% in those without such lesions (Uchida et al, Prediction of acute coronary syndromes by percutaneous coronary angioscopy in patients with stable angina, Amer Heart J 1995, 130 (2): 195-203). Despite the obvious advantages of imaging the interior of a coronary artery, the angioscope can only generally provide information about the shape and color of the interior surface of the blood vessel. The technique also requires a period of coronary occlusion and an experienced team for safe performance. The interpretation of findings with terms such as xe2x80x9cglistening yellowxe2x80x9d are particularly subjective and may provide inconsistent results.
Intracoronary ultrasound devices have been also used to characterize coronary lesions. It is possible to identify certain characteristics of these lesions beneath their intimal surface. The ability of intravascular coronary ultrasound (ICUS) to identify tissue characteristics of lesions has been established in in vitro studies with histologic correlation (Tobis J M, Mahon D, Moriuchi M et al, Intravascular ultrasonic imaging, Tex Heart Inst J 1990; 17, 181-9; Tobis J M, Mallery J, Mahon Dea, Intravascular ultrasound imaging of human coronary arteries in vivo: Analysis of tissue characterizations with comparison to in vitro histologic specimens, Circ. 1991; 83, 913-26). Fibrous plaques produce bright images with echo-free shadowing. Plaques with extracellular lipid or necrotic material displayed minimal reflectivity typically appearing in the form of hypoechoic areas, but differentiation from thrombus is quite often difficult. Such correlation studies have led to widespread use of the terms xe2x80x9chardxe2x80x9d or xe2x80x9csoftxe2x80x9d to characterize lesions based on these ultrasonic images (Hodgson J M, Reddy K G, Suneja R, Nair R N, Lesnefsky E J, Sheehan H M, Intracoronary ultrasound imaging: correlation of plaque morphology with angiography, clinical syndrome, and procedural results in patients undergoing coronary angioplasty, J Am Coll Cardiol 1993; 21, 35-44; Nissen S E, Gurley J C, Booth D C, McClure R R, Berk M R, DeMaria A N, Spectrum of intravascular ultrasound findings in atherosclerosis: wall morphology and lumen shape in CAD patients, J Am Coll Cardiol 1991; 93; Nissen S E, Gurley J C, Grines C L, Booth D C, McClure R, Berk M, Intravascular ultrasound assessment of lumen size and wall morphology in normal subjects and patients with coronary artery disease. Circ. 1991; 84, 1087-99). Unfortunately, the sensitivity and specificity of ICUS to identify particular components of a lesion, including lipid-rich regions with thin caps, is limited by the resolution of ICUS technology, and its further inability to identify chemical composition of subject tissue.
The performance of atherectomy procedures further provided significant information relating to coronary lesions. For example, in a study of atherectomy specimens in living patients with stable and unstable coronary syndromes (Moreno P R, Falk E, Palacios I F, Newell J B, Fuster V, Fallon J T, Macrophage infiltration in acute coronary syndromes: Implications for plaque rupture, Circulation 1994; 90:775-8), it was shown that macrophage-rich areas are more frequently found in patients with unstable angina and non-Q wave myocardial infarction, and are a marker of unstable atherosclerotic plaques. More recently, macrophages have been identified as a major source of tissue factor establishing a cell-mediated thrombogenicity in unstable atherosclerotic plaques (Moreno P R, Bernardi V H, Lopez-Cueller J et al, Macrophages, smooth muscle cells and tissue factor in unstable angina: Implications for cell-mediated thrombogenicity in acute coronary syndromes, Circulation 1996; 94:3090-7). There are however several limitations to the use of atherectomy specimens to study vulnerable coronary plaques. The technique is no longer in frequent use for clinical purposes, and it is anticipated that many plaques causing disease will not be stenotic, and hence cannot be sampled by atherectomy performed for clinical indications. Sampling errors may also occur if only the superficial aspect of the plaque is retrieved which obscure anatomic relationships with the rest of the plaque.
Other techniques for analyzing coronary lesions have been also proposed. Recent approaches for identification of vulnerable plaque, for example, include thermography, ultra-fast CT, magnetic resonance imaging (MRI) and optical coherence tomography (OCT) (Brezinski M E, Tearney G J, Bouma B E et al, Optical coherence tomography for optical biopsy. Circulation 1996; 93:1206-13; Brezinski M E, Tearney G J, Weissman N J et al, Assessing atherosclerotic plaque morphology: Comparison of optical coherence tomography and high frequency intravascular ultrasound, Heart 1996; 77:397-403; Toussaint J-F, LaMuraglia GMSJF, Fuster V, Kantor H L, Magnetic resonance images lipid, fibrous, calcified, hemorrhagic, and thrombotic components of human atherosclerosis in vivo, Circ. 1996; 94:932-8). Each of these approaches exhibit some relative strengths and limitations. For example, thermography has not yet been validated in vivo, and ultrafast CT is an excellent way to detect calcium but other ions and compounds are not detected. MRI is generally not suited for imaging of the small, moving coronary arteries, as opposed to the relatively sizable carotids. OCT can provide images but has not yet been reported to obtain images through blood. The limitations of these techniques for analyzing arterial diseases preclude their useful and practical application for clinical purposes.
It has been generally observed that atherosclerosis, without associated thrombosis, is often an innocuous and asymptomatic disease. Many patients with atherosclerosis can be treated surgically or by drugs with high initial success, and often have a favorable long-term prognosis. The acute manifestation of atherosclerosis, commonly occurring as myocardial infarction, unstable angina, or sudden death, usually arises when thrombus develops. These serious events typically develop at the site of plaque fissure or rupture. A number of studies have demonstrated that plaque rupture plays a pivotal role in the pathophysiology (the physiology of abnormal states and the functional changes that accompany a particular syndrome or disease) of acute coronary syndromes. Recent research indicates that it is often not the severity of stenosis (a narrowing or constriction of the diameter of an artery by plaque volume) that determines a potential outcome. It is more often the type of stenosis, or the chemical composition of the plaque, and the extent of collateral growth which becomes a determining factor. The kind of plaque, determined by composition, consistency, vulnerability and thrombogenicity, varies greatly from patient to patient, even from plaque to plaque in different locations, and there is no simple relation among plaque kind, plaque volume or stenosis severity.
Near-IR spectrometry has been performed in a limited number of applications for analyzing and detecting the presence of known indicators associated with a particular disease or condition. For example, lipids have been examined with near-IR in vitro and in vivo in gerbil brains following experimentally induced stroke, and provided the identification of nine different saturated and unsaturated fatty acids found in the gerbil brain. The changes in water content related to edema and changes in proteins were also monitored non-invasively by near-IR spectrometry in these studies. Near-IR spectrometry has also been used to analyze HDL, LDL, and cholesterol in the blood vessels of rats, and has been performed with fiber-optic probes to determine fat content in meats commercially (Nagao A, Uozumi J, Iwamoto M, Yamazaki M, Determination of fat content in meats by near-infrared reflectance spectroscopy, Chem Abstr 1985; 219697r), and to determine total body lipids in humans non-invasively (Conway J, Norris K, Bodwell C, A new approach for the estimation of body composition: Infrared interactance, Amer J Clin Nutr 1984; 1123). In addition, near-IR imaging has been used in human stroke patients to analyze atherosclerotic plaque by identifying and locating oxidized lipoprotein spectral signatures. A near-IR imaging system and parallel vector supercomputer has been used with a fiber-optic probe to produce chemical maps of the intimal surface of living arteries. Spectrometric data collected at hundreds of near-IR wavelengths were assembled into color pictures of the lipoprotein and apolipoprotein composition of early atheromas using a vectorized 3-D cellular automaton-based algorithm that operates in parallel. The nonparametric mathematics developed to identify and quantify the constituents of each voxel in the artery wall avoided the matrix factorization that generates excess error in other pattern recognition methods, and permitted analysis in a wavelength space of over 1000 dimensions using fewer than 100 calibration samples. A surface feature resolution of 5.5 micrometers and depth resolution of 6.5 micrometers were achieved with the system. Controlling the apertures on fiber-optic probes permitted the three-dimensional relationships between sample components to be determined. Data from the fiber-optic probe confirmed the injury hypothesis of lesion formation and the differing roles of HDL and LDL in cholesterol transport. Additionally, near-IR spectrometry has been used trans-arterially on exposed carotid arteries in living patients undergoing endarterectomy. Images were obtained of fibrous cap, lipids, thrombus, ulceration and necrosis with an indium antimonide focal plane array video camera (Dempsey R J, Cassis L A, Davis D G, Lodder R A, Near-infrared Imaging and Spectroscopy in Stroke Research: Lipoprotein Distribution and Disease, Ann. N.Y. Acad. Sci. 1997; 820:149-69). It has been observed that near-IR spectral analysis has chemical imaging ability, and further provides useful information and detail relating to various internal body structures such as muscle, bone, and arteries (Van de Van M, French T, Fishkin J, Gratton F, Near-infrared imaging spectroscopy of mammalian tissue in the frequency domain. Biophys J 1991; 167a). Near-IR Raman spectroscopy has been also used recently to quantitatively analyze the lipid component of human atherosclerotic plaques (Weinmann et al, Quantitative analysis of cholesterol and cholesteryl esters in human atherosclerotic plaques using near-infrared Raman spectroscopy, Atherosclerosis 1998; 140(1), 81-8) and may provide vibrational information on chemical structures without penetration of more than a few microns of water or blood. While Raman spectroscopy may provide some analysis of plaque under certain test conditions, many technical difficulties including its inherent inefficiency prevent or limit its broad application in living patients through catheter-based systems. The performance of Raman spectroscopy through a catheter is also believed to be a time-consuming and inherently inefficient process that fails to provide accurate quantification of plaque constituents.
The present invention provides reliable methods and apparatus for detecting and analyzing the composition of vulnerable plaques in living tissue with near-infrared (IR) radiation. The invention, in a non-destructive manner, may provide early detection of vulnerable plaques before the onset of an acute syndrome. Near-IR spectroscopy, a variant of the procedure used to determine the chemical composition of extraterrestrial rock samples, may identify plaques with a lipid pool and thin cap in vivo. In accordance with the invention, this may be performed through a near-IR coronary catheter for identifying vulnerable plaques in the coronary arteries of living patients. The small risk to patients associated with near-IR imaging will be balanced against the possible benefits of improved risk-stratification and effective therapy.
Another object of the present invention is to provide a method and apparatus specifically adapted to identify vulnerable plaques to thereby allow physicians to prescribe appropriate drugs that are more likely to provide effective treatment. This is a particularly important consideration when it is realized that some of the drugs or devices prescribed to treat lesions may have serious side effects which may, in some instances, be avoided altogether. Still another object of the invention is to provide a method and apparatus wherein infrared radiation of a wavelength range from about 1400-4100 nm, and more preferably from about 1600-1800 nm, is sequentially focused onto selected arterial endothelium. The reflected or scattered infrared radiation may be then detected and analyzed at high speed in accordance with the invention to not only identify vulnerable plaques, but to also evaluate the progression of disease and effectiveness of treatment.
In accordance with the principles of the present invention, improved near-IR imaging apparatus may be provided for analyzing vulnerable plaques The apparatus may not be only utilized for in vitro analysis, but may also be advantageously utilized for in vivo analysis. The apparatus may comprise a light source for transmitting simultaneously and in parallel an incident beam of light of a wavelength range from approximately 1400 to 4100 nm, and more preferably within a xe2x80x9cwater windowxe2x80x9d such as from about 1600 to 1800 nm or around 2080 nm. A fiber-optic probe may be operatively connected to the light source, and a light directing or focusing mechanism may be mounted to the distal end of the probe. The focusing mechanism may comprise a compound parabolic concentrator (CPC) that may, for example, be formed from plastic and include a polished aluminum lining. The CPC is similar to those designed for use for solar power concentration. In particular, the CPC may be adapted to compress the incident beam from the transmitting fiber-optic onto a small spot on the tissue surface undergoing analysis. Additionally, the apparatus may include detectors such as lead sulfide detectors for detecting the scattered light from the artery surface or other tissue being analyzed. In an alternative embodiment, the light directing mechanism comprises an inverted, substantially conical reflector developed from both ellipsoids of rotation and paraboloids of rotation. This reflector may direct the incident beam from the transmitting optic fiber over the tissue undergoing analysis. Additionally, light reflected or scattered by the tissue is directed or focused into receiving optic fibers so as to allow for better detection and hence, chemical analysis of the tissue. The fiber-optic catheter may also comprise separate bundles of fibers to inject light into the vessel wall at one location, and detect light scattered through the plaque and vessel wall at another location. The light injection and detection ports may be placed in contact with the vessel wall using a balloon or other device during the measurement and therapeutic processes. A portion of the transmitting fibers may also be directed onto a reflectance standard at the catheter tip and returned to a detector module for use in absorbance ratios. The apparatus may further include suitably sized catheters and equipment for high speed parallel analyzing of the spectra reflected from the tissue, and producing color images thereof. Such equipment may, for example, include a computer such as a supercomputer used at the University of Kentucky, and appropriate software such as the copyrighted Bootstrap Error-Adjusted Single-Sample Technique (BEST) Algorithm software program developed by Robert A. Lodder. Further, the fiber-optic probe may be preferably adapted for introduction into a patient to thereby allow in vivo analysis of artery walls, or in particular, lesions which may characterized as vulnerable plaques. Additional information relating to these and other applications of the present invention may be further described in U.S. Pat. No. 5,441,053 (APPARATUS AND METHOD FOR MULTIPLE WAVELENGTH ANALYSIS OF TISSUE) which is incorporated by reference herein.
A further aspect of the present invention provides various methods of analyzing arterial lesions with near-IR spectroscopy for the existence of vulnerable plaque characteristics. The method may include the steps of focusing light on the tissue to be analyzed, and detecting light reflected by the tissue. The light being focused may have a wavelength ranging from approximately 1400 to 4100; and more preferably 1600 to 1800 nm. The method may further include a step of analyzing the spectra from the tissue and producing color images thereof. Advantageously, both the focusing and analyzing steps may be performed to allow high speed data acquisition and analysis. Specifically, light having a range of wavelengths from 1400 to 4100 nm, and more preferably from 1600 to 1800 nm, may be simultaneously focused in parallel at all locations being analyzed. The analysis of the reflected light may be also completed simultaneously and in parallel for all locations being analyzed over the same range of wavelengths. As all tissues absorb light at all these wavelengths, with different tissues absorbing only a little more at some wavelengths than others, this broad band parallel approach may be useful to reduce the risk of missing unusual tissue during study. Hence, the analysis may be more accurate and complete. When identifying peaks for particular lipids and cholesterol which are known to occur at certain ranges or water windows, the analysis may be modified in accordance with the invention to more readily detect and identify the existences of vulnerable plaques. Furthermore, as the focusing of near-IR radiation and analysis are performed in parallel, the complete study may still be completed in a sufficiently short time span to allow clinical utilization as with arterial angiography. In accordance with a further method of analyzing arterial endothelium in vivo utilizing a fiber-optic probe, the method may include the initial step of introducing the probe into an artery of a patient in combination with a coronary catheter. A Nd:YAG-pumped KTP/OPO tunable near-IR laser system may be utilized as a light source for the fiber-optic catheters and related methods disclosed herein. The BEST algorithm may be used to construct chemical-composition images of the intima of the aorta in test subjects in vivo.
It is another object of the invention to provide methods and apparatus using near-IR spectrometric imaging to non-destructively locate and identify pools of LDL cholesterol which may serve as an in vivo marker for vulnerable atherosclerotic plaques. Vulnerable plaques are thought to usually contain a sizable lipid pool containing LDL covered by a thin fibrous cap. Near-IR imaging spectrometry may be performed as prescribed herein to measure the size and the chemical composition of the fibrous cap and the lipid pool. An accurate measurement of lipoprotein cholesterol is a useful first step in the intervention against diseases such as atherosclerosis and ischemic stroke, and is important in determining what constitutes a vulnerable plaque in order to derive an effective means for stabilizing such plaque. Because cholesterol is carried in lipoprotein particles that differ in size and apolipoprotein composition, this variety of lipoproteins often make non-destructive differentiation of its composition difficult in the living vessel wall. As a result, most studies focus on in vitro methodologies for determination of plaque lipoprotein composition. However, production of artifacts is common using in vitro methods and has lead to confusion in the literature. At present, there is no in vivo assay for LDL and forms of oxidized LDL (oxLDL) in solid tissue atherosclerotic plaques. More specifically, there is currently no accurate non-destructive in vivo reference assay for LDL or apolipoproteins immobilized in the walls of living human arteries. Chemical analysis of lesions in vivo would provide for the kinetic characterization of atherogenesis which contribute to the understanding of lesion formation and growth. However, the near-IR spectrometry of plaque in vivo as described herein may thus facilitate assignment of patients to specific new drug interventions that may affect the course of atherosclerosis (such as TPA, which acts to block thrombi, Enlimomab, which acts to block granulocyte adhesion to the blood-vessel wall, Citicoline, which reduces free fatty acids, Lubeluzole, which interferes with the effects of nitric oxide, Tirilizad, which acts as a free-radical scavenger, or bFGF, which acts on growth factors) and/or surgical interventions such as bypass grafts or angioplasty and stents. The basic near-IR imaging techniques provided herein are based at least in part on the principle that many organic molecules absorb light in the near-IR spectrum in a specific manner. This creates unique reflectance spectra that can be analyzed to perform a non-destructive chemical analysis of tissue either through a microscope, or at a distance through a fiber-optic catheter. A Nd:YAG-pumped KTP/OPO laser system may be used with spectrometric catheters for use in analyzing atherosclerosis and markers of vulnerable plaque. The near-IR spectrometric catheter may be thus used for early detection of LDL uptake in the arterial wall even before the appearance of visible fatty streaks. Another object of the invention therefore is to provide near-IR laser spectrometric assays of plaque which may be performed with cardiac catheters in vivo to facilitate the assignment of patients to specific drug or surgical interventions that are selected to match their individual vulnerable plaque characteristics.
Other aspects of the invention are directed to the role of group V secretory phospholipase A2 (sPLA2), an important enzyme in inflammatory processes, in the generation of vulnerable atherosclerotic plaques. Near-IR imaging may be used to identify predetermined compounds such as sPLA2, and to survey for new compounds. For example, lysophosphatidylcholine (LPC) is a major product of sPLA2 action. Since there are no specific antibodies to LPC that could be used for immunohistochemical studies, its localization in various regions of plaque may be determined by near-IR imaging of histologic sections. Moreover, near-IR spectra may be obtained for lesions from animal studies overexpressing sPLA2 activity. These spectra, which may reflect a combination of elements potentially associated with vulnerability, can be compared with the spectra obtained in patients at sites proven to be vulnerable by occurrence of subsequent events. Spectra from the animal studies may thus identify a compound not yet suspected to be associated with vulnerability in humans. The role of serum amyloid A (SAA) has been also shown to be an important cofactor for sPLA2 activity, and associated with clinical events. Its role may be further elucidated by the invention, and will be measured in patients undergoing near-IR imaging. The overall importance of sPLA2 as a determinant of plaque vulnerability may be further recognized if sPLA2 is indeed determined to play a major role in this condition. An sPLA2 inhibitor may be thus used as first-line therapy for patients found to have a vulnerable plaque. In any event, the final decision on therapy in patients will be made on the basis of the best information available at the time of treatment. The invention provides an increased understanding as to the diagnosis, and treatment, of vulnerable coronary plaques. This information concerning sPLA2 may provide new therapeutic opportunities such as the development of a specific inhibitor of the isoform of the enzyme located in macrophages. The development of a low-risk method to identify vulnerable plaques in high-risk patients undergoing PTCA/stenting would greatly aid in the conduct of studies to diminish that risk with specific drug therapy. Individuals at increased risk of disruption of a vulnerable plaque may be assisted by the invention which creates the foundation for the development of interventions that prevent the sudden onset of a catastrophic coronary event.
It is another object of the invention to provide near-IR imaging of plaque composition and vulnerability in vivo. Near-IR spectroscopy may identify vulnerable lesions in the coronary arteries of living patients. In particular, vulnerable coronary plaque may be detected because of the unique advantages provided by the catheter-based near-IR imaging systems described herein despite the general difficulty in imaging coronary lesions. These catheter-based near-IR imaging systems provide possible prospective identification of vulnerable coronary artery plaques in living patients. Particular investigations may be conducted in accordance with the invention: to obtain additional calibration and blinded validation of near-IR imaging in ex vivo human autopsy specimens (blocks from aortas and coronary arteries); to test the ability of catheter-based near-IR imaging to detect vulnerable aortic plaque in vivo (in rabbits) with diet-induced atherosclerosis; to perform near-IR catheter-based mapping of coronary artery chemical composition in patients undergoing PTCA and/or stenting; and to identify rapid lesion progression by angiography and clinical events during subsequent years. When potentially high-risk patients are identified with near-IR signatures of plaques with lipid pools and thin caps, for example, they may be subject to a further therapy study to stabilize vulnerable plaques. Another object of the invention is to thus provide therapeutic methods and apparatus to stabilize plaques that have been characterized as vulnerable by using near-IR therapy to promote fibrosis or thickening of the thin fibrous caps covering these lipid pools to prevent their rupture or leakage. The subsequent treatments to be administered may further include an orally active matrix metalloproteinase inhibitor (MMPI), and, possibly, an inhibitor of Group v secretory phospholipase 2 (sPLA2). Patients may also be selected for intensive lipid lowering therapies if they were found to have vulnerable plaques.
In accordance with another aspect of the invention, it is further possible to determine the relationship between the prospective near-IR chemical map of the human coronary tree, and the rapid progression of coronary lesions as of one-year later which may be documented by angiographic and/or autopsy findings. These findings may be provided from a study involving a relatively large number of patients such as 600 or more undergoing angioplasty wherein three major coronary arteries are scanned for the presence of vulnerable plaques as described herein. There may be follow-up procedures for up to several years to determine the occurrence of subsequent cardiac events. The near-IR signature of sites or lesions that eventually progress to an event may be considered the near-IR sign or indicator of plaque vulnerability. This relationship may be used to construct a near-IR index of true vulnerability of coronary plaques in living patients. Various embodiments of the invention make this particularly feasible in that near-IR spectroscopy may identify plaques with a lipid pool and thin cap in vivo, and may be performed through a coronary catheter as described herein. A validated, prospective, near-IR index of vulnerability may be thus developed in accordance with the invention. Effective stabilization therapy may be identified thereafter, and may be widely used in the treatment of high-risk patients undergoing coronary interventions. Collagen degradation by MMPs and plaque inflammation have been demonstrated in atherosclerotic tissue, and well-tolerated, orally active inhibitors are also available. Studies of plaque stabilization in such patients may further yield information of great value for all individuals at risk of plaque disruption and coronary events. Additional objects and advantages of the invention will become apparent to those skilled in the art upon examination of the foregoing description of the invention which may be modified without departing from the scope of the invention.